There is consensus that low physical activity (PA) levels increase the risk of colon cancer in humans, particularly among individuals with elevated adiposity. However, the precise mechanism(s) of action for these associations have not been established. Although initial evidence indicates a role for inflammatory markers (e.g., prostaglandin-E2) among individuals with low PA or high levels of adiposity, simple descriptions of the patterns of cell proliferation and apoptosis, or markers of these processes, across PA levels are not available. Accordingly, the first aim of this proposal is to develop and refine hypotheses concerning the biologic mechanisms through which PA reduces risk for colon cancer by: (a) evaluating the independent and combined associations of physical activity/fitness, adiposity, and metabolic predictors (blood glucose, triglycerides) of colon cancer risk in the Aerobics Center Longitudinal Study (Dallas, TX) using a nested-case control design (N=600), and (b) evaluating the independent and combined associations of PA and adiposity on biomarkers for colon cancer associated with inflammation (cyelooxygenase-2), cell proliferation (mib 1), and apoptosis (bax, bak, bcl2) in cross-sectional analyses of the Markers of Adenomatous Polyps II Study (N=200, Columbia, SC). Results from these analyses will be used to select up to 10 biomarkers for evaluation in a longitudinal pilot study. The second aim is to quantify the effect of changes in PA levels on selected biomarkers in a randomized trial (N=50, intervention vs. usual care) among adults not meeting current PA recommendations. Intervention participants will receive a 12-month home-base walking intervention based on Social Cognitive Theory that includes monthly phone contact with a health educator. Potential mediators and moderators of behavior change will be quantified (e.g., self-efficacy, social support). PA goals for the intervention group will be to walk briskly at least 5 times per week for 40-45 minute per day (1125 kcal/wk). Outcome biomarker measures will be obtained via rectal biopsy at baseline and 12-months. In summary, the series of investigations outlined in this proposal will examine the independent and combined effects of PA and energy balance (adiposity) on colon cancer and adenomatous polyp outcomes, and relate these findings to parallel analyses on tissue biomarker outcomes describing the biologic mechanisms linking PA and energy balance to colon cancer risk. This work will extend our understanding of the biological mechanisms underlying these causal relationships.